Aluminum (Al) is a common contaminant in many medical solutions. This is in part the result of the widespread distribution of aluminum in the environment. In addition, some medical solutions contain compounds that react strongly with aluminum and extract this metal from the surroundings, e.g. from the walls of glass containers. This strong binding increases the Al contamination and makes it much more difficult to remove the aluminum from these solutions.
Healthy adults are generally protected against oral aluminum toxicity by the fact that less than 1% of an oral dose of aluminum is absorbed from the intestine. In addition, the urinary excretion of aluminum is relatively effective for persons with normal kidney function.
There is a special concern regarding aluminum exposure to premature neonates. These infants routinely require several or more days of parenteral nutrition (PN) until they can tolerate oral feeding. The PN bypasses the normal protection associated with low intestinal absorption of Al. In addition, these infants often have underdeveloped kidney function (the primary route of Al elimination), which impedes the excretion of the aluminum contained in the PN solution.
It is well known that some of the small volume parenteral (SVP) solutions used to prepare the final PN solutions are heavily contaminated with aluminum. Poole, co-workers and others have extensively documented the Al content of SVP solutions, as shown in Table 1.
TABLE 1Aluminum content of the most contaminated SVP solutionsSolution Aluminum concentration (micrograms/L)Calcium gluconate3234 and 1920 to 34951, 4900 (new) andand 19,40036145 (old glass ampoules)2, 9205Potassium phosphate8280 and 3650 to 16,8201Sodium Phosphate622 and 17 to 32811Multi-trace elements414 and 101 to 7391, 1049 and 20653Potassium Lactate15004Potassium Acetate42 and 11 to 11201Sodium acetate83 and 54 to 13811From Poole et al., Pediatr. Gastroenterol. Nutr. 2010, 50: 208; Poole et al., J. Pediatr. Pharmacol. Ther. 2011, 16: 92.2From Beaney and Smeaton, Congress of the European Association of Hospital Pharmacists, 2010.3From de Oliveira et al., JPEN J Parenter Enteral Nutr 2010, 34: 322-328.4From Advenier et al., J. Pediatr. Gastroenterol. Nutr. 2003, 36: 448.
Because of the relative volumes of each of these solutions included in a typical PN preparation, most of the final Al content originates from the calcium gluconate SVP solution. It is noteworthy that the Al content of calcium gluconate can vary widely, depending on the commercial provider. Reported Al concentrations range from 1920 to 19,400 micrograms/L. At a typical concentration of 4,000 micrograms/L, it is estimated that calcium gluconate contributes about 80% of the aluminum in the final PN solution (Mouser et al., Am. J. Health-Syst. Pharm., 1998, 55: 1071).
The FDA has formally recognized the problem of potential Al toxicity to premature infants. It has established a safe level of Al exposure as 4 to 5 micrograms/kg/d. However, it is widely recognized that currently the U.S. pharmaceutical industry cannot supply SVP component solutions that allow pediatric pharmacists to prepare PN solutions that meet this exposure limit.
Other patient populations at risk include, but are not limited to, children with malabsorption syndrome, dialysis patients, elderly patients (due to a weakened GI protective barrier and/or normal renal function deterioration) and burn patients (due to Al-contaminated albumin to maintain oncotic pressure). In addition, critically ill infants and children require parenteral calcium replacement because of hypocalcemia, especially after cardiac surgery. More specifically, the amount of calcium required, provided as calcium gluconate, would lead to exposure to much greater than 5 micrograms of aluminum per kg per day. Removal of aluminum from these parenteral infusions would minimize potential aluminum-induced toxicities.
Disclosed herein is a single-use filter to remove aluminum from a solution as it passes through the filter. The body of the filter is filled with a specialized chelator, such as trihydroxamate chelating resin, described in our previous U.S. Pat. Nos. 7,932,326 and 8,066,883 and U.S. patent application Ser. No. 13/278,498 the full disclosures of which are incorporated herein by reference. The other components of the filter are designed to produce a controlled fluid flow rate, using a partially evacuated vial and a flow restriction/flow controller tube that has an internal diameter and length, that when paired with the extent of vacuum in the partially evacuated vial, achieves a desired flow rate. The filter is designed to connect to the evacuated vial and the vial of the source SVP solution.
Chelating resins are not new. Chelex 100® is a polystyrene resin which has iminodiacetic acid functional groups covalently linked to the resin. It is relatively non-selective, and thus is widely used to bind a large number of metal ions. However, we have determined that this type of generic chelating resin is not effective for removing aluminum from solutions such as calcium gluconate.
The concept of a flow-through filter for removing contaminants from aqueous solutions is also widely used. There are many examples of point-of-use filters for home faucets to remove both metal ions and organic contaminants. These typically remove metal ions by simple cation exchange. Thus they are not designed to compete against strong Al-binding ligands in the solution. More specialized chelating resins have been used in filters in research labs, but they have not been applied to the removal of aluminum from SVP solutions.
Flow-through filters have been used in medical settings. The chelating agent desferrioxamine has been physically imbedded into a hollow-fiber filter for the extracorporeal removal of iron and aluminum from blood during hemodialysis. Desferrioxamine has also been covalently bound to silica for the extracorporeal removal of metal ions from blood. Neither of these filters has been suggested for use in a pharmaceutical setting for removing aluminum from SVP solutions.